The eccrine sweat gland, whose primary function is thermoregulation, is one of the major cutaneous appendages. Its frequent disorders include hyperhidrosis (HH, including that of the palms and soles), anhidrosis (AH) with or without associated compensatory HH or heat intolerance, and dyshidrosis. All of these conditions are as incapacitating to patients as any other dermatological disorder, yet these disorders have never been studied and thus merit in-depth investigation. Many of the following proposed studies are predicated on recent observations from our laboratory; 1. HH is frequently associated with dramatic glandular hypertrophy. Yet, we know very little about the regulation of glandular growth, the pathophysiology of HH, and the functional deviation, if any, of HH glands. The effects of neurotransmitters, growth factors, and components of sweat on glandular growth will be first studied. 2. Human sweat from the trunk contains a high level (500 pg/ml) of interleukin (IL)-1alpha, which subsequently initiates a cytokine network in the sweat gland. The function of this cytokine network needs to be investigated. 3. Palm sweat contains up to 10 ng/ml IL-1alpha. Since sweat retention is most likely associated with dyshidrosis, the possible role of massive cytokine reflux into the skin must be investigated as the pathogenesis of dyshidrosis. The abnormal regulation of IL synthesis by the palm sweat gland also needs to be clarified. 4. Palm sweat glands from normal individuals behave like cystic fibrosis (CF) sweat glands as indicated by their high ductal bioelectric potential, high sweat Na concentration, and decreased or absent sweating responses to cAMP. The mechanism causing these unique characteristics of palm sweat glands should be examined. 5. AH is often associated with compensatory HH or heat intolerance. The seemingly simple task of differentiating the causes of AH has proven to be very problematical. To answer the questions just posed requires considerable experience and expertise. As the only sweat gland research laboratory dedicated to studying the basic physiological, biochemical, and molecular biological aspects of glandular function, we are proficient with the wide variety of methodologies needed to examine the fundamental mechanisms of normal and abnormal regulation of sweat gland function. These methodologies include; sweat gland isolation, in vitro sweat induction and ductal perfusion, preparation of dissociated cells for patch clamp studies of ionic channels in the membrane and for the determination of [Ca]i and [pH]i, immunohistochemistry to study expression of channel proteins and growth-related proteins, in situ hybridization to detect mRNA, RNAase protection assay of mRNA, Northern blot analysis, and semiquantitative polymerase chain reaction. The proposed studies will enhance our understanding of the pathogenesis of sweat gland disorders and help us design new strategies for more effective therapeutic interventions.